Trials stopped: PAVE and Phambili

In the wake of the STEP trial, PAVE 100, a planned efficacy trial of a vaccine with similarities to the STEP vaccine, was slimmed down to a safety trial. At the same time, Phambili, intended to be a companion trial to STEP using a vaccine tailored to the southern African population, was stopped.

PAVE was originally designed to include 8500 volunteers in the United States, South America, the Caribbean and Eastern and Southern Africa. The study was to begin US recruitment in October 2007 but was postponed following the decision to halt immunisations in the STEP study.

PAVE was designed to study a different vaccine product, called VRC, which consisted of a DNA-based plasmid vaccine and a follow-up booster vaccine that used an adenovirus to deliver recombinant HIV sequences from a variety of HIV sub-types.

There was little scientific confidence that PAVE would lead on directly to licensing of the VRC vaccine. Instead, the study would at best have provided further information to the field about immune responses. An advisory group recommended in May 2008 that a smaller version of PAVE 100 should go ahead, which would measure if the vaccine reduced viral load in people who became infected despite vaccination.

A suggestion of such a reduction, at least in women, had been seen in the Phambili trial, which was stopped in the wake of STEP.¹

The Phambili trial was a companion to the STEP trial, testing the Ad5 vaccine in high-risk men and women in South Africa, and was intended as a test of the vaccine’s potential for cross-clade protection. The Merck vaccine was based on HIV-1 subtype B, but the dominant subtype of HIV circulating in South Africa is subtype C.

The study was designed to recruit 3000 high-risk men and women at five sites across South Africa, but was halted when the decision was reached to close the STEP study. By this point the study had recruited 801 participants.

Dr Glenda Gray reported interim results to December 2008 at the Paris AIDS Vaccine conference in October 2009. At this point 90% of participants were still undergoing follow-up; 80% of participants had received at least two vaccinations before study vaccinations were halted.

Dr Gray reported that women who became infected despite vaccination showed a trend towards a lower viral load setpoint (nearly fourfold or 0.57 log, p=0.09) than women who became infected in the placebo group. However, the numbers involved were small, and the difference in viral load setpoints was not matched by a sustained difference in CD4 cell counts. Overall, the viral load and CD4 trends showed no significant difference, said Dr Gray, but the viral load setpoint effect in women required further study.

The annual infection rate was 4.69% in the vaccine group and 3.8% in the placebo group, with a hazard ratio of 1.26 (95% confidence interval 0.76 to 2.10, p=0.37). Although none of the differences in infections or infection rates between the two arms were statistically significant, there were always more infections in the vaccine arm, no matter how the data were compared.

David Baltimore, President of the American Association for the Advancement of Science (AAAS) and the discoverer of reverse transcriptase, made a pessimistic assessment of the state of HIV vaccine research to the AAAS Conference in February 2008. His remarks were taken up by the world’s press.²

He told the conference that the failure of every promising approach to an HIV vaccine had led many scientists to wonder whether it would ever be possible to create one. No research projects currently underway, including his own, had any realistic prospect of producing a vaccine for at least a decade, and success might take even longer, he said. “The community is depressed,” he admitted, “because we see no hopeful route to success.”

“It’s such a sad topic,” he said of the search for an AIDS vaccine. “We have been trying to make an HIV vaccine since the day HIV was discovered. In 1984, we were told that as the virus had been found, a vaccine should be just around the corner. History was on our side - we have been able to make vaccines versus almost all the viruses that affect humans. But we are no closer to a vaccine now than we were then.

“Every year since then, we have been saying it is at least 10 years away. I still think it is at least 10 years away. And if it has been 10 years away for 20 years, you might ask does that really mean it will never happen? I’m not prepared to say that, because I don’t want to take a pessimistic stand. This is too important to give up on. Our lack of success may be understandable, but it is not acceptable.”